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Background: There is a need to increase the capacity and capability of musculoskeletal researchers to design, conduct, and report high-quality clinical trials. The objective of this study was to identify and prioritise clinical trial learning needs of musculoskeletal researchers in Australia and Aotearoa New Zealand. Findings will be used to inform development of an e-learning musculoskeletal clinical trials course., Methods: A two-round online modified Delphi study was conducted with an inter-disciplinary panel of musculoskeletal researchers from Australia and Aotearoa New Zealand, representing various career stages and roles, including clinician researchers and consumers with lived experience of musculoskeletal conditions. Round 1 involved panellists nominating 3-10 topics about musculoskeletal trial design and conduct that they believe would be important to include in an e-learning course about musculoskeletal clinical trials. Topics were synthesised and refined. Round 2 asked panellists to rate the importance of all topics (very important, important, not important), as well as select and rank their top 10 most important topics. A rank score was calculated whereby higher scores reflect higher rankings by panellists., Results: Round 1 was completed by 121 panellists and generated 555 individual topics describing their musculoskeletal trial learning needs. These statements were grouped into 37 unique topics for Round 2, which was completed by 104 panellists. The topics ranked as most important were: (1) defining a meaningful research question (rank score 560, 74% of panellists rated topic as very important); (2) choosing the most appropriate trial design (rank score 410, 73% rated as very important); (3) involving consumers in trial design through to dissemination (rank score 302, 62% rated as very important); (4) bias in musculoskeletal trials and how to minimise it (rank score 299, 70% rated as very important); and (5) choosing the most appropriate control/comparator group (rank score 265, 65% rated as very important)., Conclusions: This modified Delphi study generated a ranked list of clinical trial learning needs of musculoskeletal researchers. Findings can inform training courses and professional development to improve researcher capabilities and enhance the quality and conduct of musculoskeletal clinical trials., (© 2024. The Author(s).)

Background: The number of older people is increasing worldwide and public expenditure on residential aged care facilities (ACFs) is expected to at least double, and possibly triple, by 2050. Co-ordinated and timely care in residential ACFs that reduces unnecessary hospital transfers may improve residents' health outcomes and increase satisfaction with care among ACF residents, their families and staff. These benefits may outweigh the resources needed to sustain the changes in care delivery and potentially lead to cost savings. Our systematic review comprehensively and systematically presents the available evidence of the effectiveness, safety and cost-effectiveness of alternative models of providing health care to ACF residents., Objectives: Main objective To assess the effectiveness and safety of alternative models of delivering primary or secondary health care (or both) to older adults living in ACFs. Secondary objective To assess the cost-effectiveness of the alternative models., Search Methods: We searched CENTRAL, MEDLINE, Embase, five other databases and two trials registers (WHO ICTRP, ClinicalTrials.gov) on 26 October 2022, together with reference checking, citation searching and contact with study authors to identify additional studies., Selection Criteria: We included individual and cluster-randomised trials, and cost/cost-effectiveness data collected alongside eligible effectiveness studies. Eligible study participants included older people who reside in an ACF as their place of permanent abode and healthcare professionals delivering or co-ordinating the delivery of healthcare at ACFs. Eligible interventions focused on either ways of delivering primary or secondary health care (or both) or ways of co-ordinating the delivery of this care. Eligible comparators included usual care or another model of care. Primary outcomes were emergency department visits, unplanned hospital admissions and adverse effects (defined as infections, falls and pressure ulcers). Secondary outcomes included adherence to clinical guideline-recommended care, health-related quality of life of residents, mortality, resource use, access to primary or specialist healthcare services, any hospital admissions, length of hospital stay, satisfaction with the health care by residents and their families, work-related satisfaction and work-related stress of ACF staff., Data Collection and Analysis: Two review authors independently selected studies for inclusion, extracted data, and assessed risk of bias and certainty of evidence using GRADE. The primary comparison was any alternative model of care versus usual care., Main Results: We included 40 randomised trials (21,787 participants; three studies only reported number of beds) in this review. Included trials evaluated alternative models of care aimed at either all residents of the ACF (i.e. no specific health condition; 11 studies), ACF residents with mental health conditions or behavioural problems (12 studies), ACF residents with a specific condition (e.g. residents with pressure ulcers, 13 studies) or residents requiring a specific type of care (e.g. residents after hospital discharge, four studies). Most alternative models of care focused on 'co-ordination of care' (n = 31). Three alternative models of care focused on 'who provides care' and two focused on 'where care is provided' (i.e. care provided within ACF versus outside of ACF). Four models focused on the use of information and communication technology. Usual care, the comparator in all studies, was highly heterogeneous across studies and, in most cases, was poorly reported. Most of the included trials were susceptible to some form of bias; in particular, performance (89%), reporting (66%) and detection (42%) bias. Compared to usual care, alternative models of care may make little or no difference to the proportion of residents with at least one emergency department visit (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.84 to 1.20; 7 trials, 1276 participants; low-certainty evidence), but may reduce the proportion of residents with at least one unplanned hospital admission (RR 0.74, 95% CI 0.56 to 0.99, I 2 = 53%; 8 trials, 1263 participants; low-certainty evidence). We are uncertain of the effect of alternative models of care on adverse events (proportion of residents with a fall: RR 1.15, 95% CI 0.83 to 1.60, I² = 74%; 3 trials, 1061 participants; very low-certainty evidence) and adherence to guideline-recommended care (proportion of residents receiving adequate antidepressant medication: RR 5.29, 95% CI 1.08 to 26.00; 1 study, 65 participants) as the certainty of the evidence is very low. Compared to usual care, alternative models of care may have little or no effect on the health-related quality of life of ACF residents (MD -0.016, 95% CI -0.036 to 0.004; I² = 23%; 12 studies, 4016 participants; low-certainty evidence) and probably make little or no difference to the number of deaths in residents of ACFs (RR 1.03, 95% CI 0.92 to 1.16, 24 trials, 3881 participants, moderate-certainty evidence). We did not pool the cost-effectiveness or cost data as the specific costs associated with the various alternative models of care were incomparable, both across models of care as well as across settings. Based on the findings of five economic evaluations (all interventions focused on co-ordination of care), we are uncertain of the cost-effectiveness of alternative models of care compared to usual care as the certainty of the evidence is very low., Authors' Conclusions: Compared to usual care, alternative models of care may make little or no difference to the number of emergency department visits but may reduce unplanned hospital admissions. We are uncertain of the effect of alternative care models on adverse events (i.e. falls, pressure ulcers, infections) and adherence to guidelines compared to usual care, as the certainty of the evidence is very low. Alternative models of care may have little or no effect on health-related quality of life and probably have no effect on mortality of ACF residents compared to usual care. Importantly, we are uncertain of the cost-effectiveness of alternative models of care due to the limited, disparate data available., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Research has shown a strong relationship between hallucinations and suicidal behaviour in general population samples. Whether hallucinations also index suicidal behaviour risk in groups at elevated risk of suicidal behaviour, namely in individuals with a sexual assault history, remains to be seen., Aims: We assessed whether hallucinations were markers of risk for suicidal behaviour among individuals with a sexual assault history., Methods: Using the cross-sectional 2007 ( N = 7403) and 2014 ( N = 7546) Adult Psychiatric Morbidity Surveys, we assessed for an interaction between sexual assault and hallucinations in terms of the odds of suicide attempt, as well as directly comparing the prevalence of suicide attempt in individuals with a sexual assault history with v. without hallucinations., Results: Individuals with a sexual assault history had increased odds of hallucinations and suicide attempt compared to individuals without a sexual assault history in both samples. There was a significant interaction between sexual assault and hallucinations in terms of the odds of suicide attempt. In total, 14-19% of individuals with a sexual assault history who did not report hallucinations had one or more suicide attempt. This increased to 33-52% of individuals with a sexual assault history who did report hallucinations (2007, aOR = 2.85, 1.71-4.75; 2014, aOR = 4.52, 2.78-7.35)., Conclusions: Hallucinations are a risk marker for suicide attempt even among individuals with an elevated risk of suicidal behaviour, specifically individuals with a sexual assault history. This finding highlights the clinical significance of hallucinations with regard to suicidal behaviour risk, even among high-risk populations.

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.

Current strategies to predict psychosis identify only a small proportion of individuals at risk. Additional strategies are needed to increase capacity for pre-diction and prevention of serious mental illness, ideally during childhood and adolescence. One possible approach would be to investigate systems in which psychosis risk factors are concentrated during childhood. One notable such system is represented by Child and Adolescent Mental Health Services (CAMHS). Although psychotic disorders are uncommon in CAMHS, many risk factors for psychosis are highly prevalent in young people who enter this system. We hypothesized, therefore, that youth attending CAMHS would be a high-risk group for psychosis if followed into adulthood and, furthermore, that CAMHS systems would capture a substantial proportion of future psychosis cases. We constructed a total population cohort study of all Finns born in 1987 (N=55,875), linking together extensive register data on health care contacts from birth through age 28 years. We identified all individuals diagnosed with a psychotic or bipolar disorder by age 28 (N=1,785). The risk of psychosis/bipolar disorder by age 28 years was 1.8% for individuals who had not attended CAMHS during childhood or adolescence, whereas it was 12.8% for those with a history of any outpatient CAMHS contact (odds ratio, OR=7.9, 95% CI: 7.2-8.7). Furthermore, the risk of psychosis/bipolar disorder by age 28 years was 2.3% for individuals without a history of inpatient CAMHS admission, whereas it was 24.0% for those with a history of inpatient CAMHS admission (OR=13.3, 95% CI: 11.9-14.9), and 36.5% for those with a history of inpatient CAMHS admission in adolescence (age 13-17 years) (OR=24.2, 95% CI: 21.2-27.6). Individuals who attended CAMHS but received no mental disorder diagnosis had an equally high risk of subsequently developing a psychosis/bipolar disorder as individuals who did receive a diagnosis (OR=0.9, 99.5% CI: 0.7-1.1). Compared to other CAMHS attendees, individuals who developed psychosis or bipolar disorder were more likely to have had an initial CAMHS diagnosis of depressive or other mood disorder (OR=2.3, 99.5% CI: 1.6-3.0) and disruptive behaviour disorder (OR=1.7, 99.5% CI: 1.2-2.5). Of all psychosis/bipolar diagnoses by age 28 years, 50.2% occurred in individuals who had, at some point in childhood or adolescence, attended CAMHS, indicating that CAMHS represent not only a high-risk but also a high-capacity system for prediction of psychosis/bipolar disorder. These findings suggest an enormous, untapped potential for large-scale psychosis/bipolar disorder prediction and prevention research within existing specialist CAMHS., (© 2022 World Psychiatric Association.)

Background: Community studies have found a relatively high prevalence of hallucinations, which are associated with a range of (psychotic and non-psychotic) mental disorders, as well as with suicidal ideation and behaviour. The literature on hallucinations in the general population has largely focused on adolescents and young adults., Aims: We aimed to explore the prevalence and psychopathologic significance of hallucinations across the adult lifespan., Method: Using the 1993, 2000, 2007 and 2014 cross-sectional Adult Psychiatric Morbidity Survey series (N = 33 637), we calculated the prevalence of past-year hallucinations in the general population ages 16 to ≥90 years. We used logistic regression to examine the relationship between hallucinations and a range of mental disorders, suicidal ideation and suicide attempts., Results: The prevalence of past-year hallucinations varied across the adult lifespan, from a high of 7% in individuals aged 16-19 years, to a low of 3% in individuals aged ≥70 years. In all age groups, hallucinations were associated with increased risk for mental disorders, suicidal ideation and suicide attempts, but there was also evidence of significant age-related variation. In particular, hallucinations in older adults were less likely to be associated with a cooccurring mental disorder, suicidal ideation or suicide attempt compared with early adulthood and middle age., Conclusions: Our findings highlight important life-course developmental features of hallucinations from early adulthood to old age.

Impaired synaptic neurotransmission may underly circuit alterations contributing to behavioral autism spectrum disorder (ASD) phenotypes. A critical component of impairments reported in somatosensory and prefrontal cortex of ASD mouse models are parvalbumin (PV)-expressing fast-spiking interneurons. However, it remains unknown whether PV interneurons mediating hippocampal networks crucial to navigation and memory processing are similarly impaired. Using PV-labeled transgenic mice, a battery of behavioral assays, in vitro patch-clamp electrophysiology, and in vivo 32-channel silicon probe local field potential recordings, we address this question in a Cntnap2-null mutant mouse model representing a human ASD risk factor gene. Cntnap2 -/- mice show a reduction in hippocampal PV interneuron density, reduced inhibitory input to CA1 pyramidal cells, deficits in spatial discrimination ability, and frequency-dependent circuit changes within the hippocampus, including alterations in gamma oscillations, sharp-wave ripples, and theta-gamma modulation. Our findings highlight hippocampal involvement in ASD and implicate interneurons as a potential therapeutical target., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)